Abstract
Bruton’s tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors (n = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors (p ≤ 0.05) and overall survival (OS) of patients with grade III gliomas (p ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
Highlights
Protein tyrosine kinases (PTKs) play an important role in the control of many cellular processes and signaling, including cell migration, metabolism, survival, cell proliferation and differentiation (Endicott et al, 2012)
We previously showed that p65BTK is a potent oncogene acting downstream of RAS and its targeting by ibrutinib has an anti-proliferative effect on CRC cell lines (Grassilli et al, 2016)
These results suggest that p65BTK could represent an ideal target for new advanced drugs: p65BTK targeted inhibition was reported in ovarian (Conconi et al, 2017) and colon cancer, restoring the apoptotic response to chemotherapy (Ianzano et al, 2016)
Summary
Protein tyrosine kinases (PTKs) play an important role in the control of many cellular processes and signaling, including cell migration, metabolism, survival, cell proliferation and differentiation (Endicott et al, 2012). Bruton’s tyrosine-kinase (BTK) is a non-receptor tyrosine kinase (Mohamed et al, 2009), belonging to the Tec family of kinases (Smith et al, 2001), expressed in all cell lineages of the hematopoietic system, except for T cells. BTK is a 77KD protein essential for B-lymphocyte development, differentiation and signaling (Satterthwaite et al, 1998) and is currently involved in both physiological and oncogenic pathways through B-cell receptor regulation (Seda and Mraz, 2015). The BTK inhibitor ibrutinib is a promising new therapeutic strategy for glioma, blocking the proliferation, migration and invasion properties and inducing apoptosis and autophagy of glioma cells, targeting the Akt/mTOR pathway (Wang et al, 2017)
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